DE3203307A1 - Phosphonates, and pharmaceutical compounds containing them - Google Patents
Phosphonates, and pharmaceutical compounds containing themInfo
- Publication number
- DE3203307A1 DE3203307A1 DE19823203307 DE3203307A DE3203307A1 DE 3203307 A1 DE3203307 A1 DE 3203307A1 DE 19823203307 DE19823203307 DE 19823203307 DE 3203307 A DE3203307 A DE 3203307A DE 3203307 A1 DE3203307 A1 DE 3203307A1
- Authority
- DE
- Germany
- Prior art keywords
- chlorophenyl
- fluorophenyl
- pyrazolyl
- group
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 title description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 8
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract 4
- 229910052801 chlorine Inorganic materials 0.000 claims abstract 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract 2
- 125000004423 acyloxy group Chemical group 0.000 claims abstract 2
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract 2
- 150000001340 alkali metals Chemical group 0.000 claims abstract 2
- 125000003277 amino group Chemical group 0.000 claims abstract 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract 2
- 229910052794 bromium Inorganic materials 0.000 claims abstract 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract 2
- 239000000460 chlorine Substances 0.000 claims abstract 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract 2
- 229910052731 fluorine Inorganic materials 0.000 claims abstract 2
- 239000011737 fluorine Substances 0.000 claims abstract 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 35
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 32
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 10
- -1 2- [4- (4-Chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] -1-hydroxy-ethene-phosphonic acid Chemical compound 0.000 claims description 8
- MJUJXFBTEFXVKU-UHFFFAOYSA-N diethyl phosphonate Chemical compound CCOP(=O)OCC MJUJXFBTEFXVKU-UHFFFAOYSA-N 0.000 claims description 5
- YLFBFPXKTIQSSY-UHFFFAOYSA-N dimethoxy(oxo)phosphanium Chemical compound CO[P+](=O)OC YLFBFPXKTIQSSY-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229920001567 vinyl ester resin Polymers 0.000 claims description 3
- GDMUDZGLONYSQR-UHFFFAOYSA-N OC(P(O)(O)=O)=CC1=CN(C2=CC=CC=C2)N=C1C(C=C1)=CC=C1Cl Chemical compound OC(P(O)(O)=O)=CC1=CN(C2=CC=CC=C2)N=C1C(C=C1)=CC=C1Cl GDMUDZGLONYSQR-UHFFFAOYSA-N 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims 1
- 239000013543 active substance Substances 0.000 abstract 1
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- 239000000203 mixture Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- BCLXJQOHLUTWTC-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)pyrazol-3-yl]acetyl chloride Chemical compound C1=CC(F)=CC=C1N1N=C(CC(Cl)=O)C(C=2C=CC(Cl)=CC=2)=C1 BCLXJQOHLUTWTC-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ILOAWYFOASVKNT-UHFFFAOYSA-N C(C)OP(OCC)(=O)C(=CC1=NN(C=C1C1=CC=C(C=C1)Cl)C1=CC=C(C=C1)F)O Chemical compound C(C)OP(OCC)(=O)C(=CC1=NN(C=C1C1=CC=C(C=C1)Cl)C1=CC=C(C=C1)F)O ILOAWYFOASVKNT-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- KAZRLJCDXRMZTJ-UHFFFAOYSA-N [2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)pyrazol-3-yl]-1-hydroxy-1-phosphonoethyl]phosphonic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=NN(C=2C=CC(F)=CC=2)C=C1C1=CC=C(Cl)C=C1 KAZRLJCDXRMZTJ-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000002456 anti-arthritic effect Effects 0.000 description 2
- 230000002500 effect on skin Effects 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- MXYOPVWZZKEAGX-UHFFFAOYSA-N 1-phosphonoethylphosphonic acid Chemical compound OP(=O)(O)C(C)P(O)(O)=O MXYOPVWZZKEAGX-UHFFFAOYSA-N 0.000 description 1
- YSQLFGQECCZYNG-UHFFFAOYSA-N 2-[3-(4-chlorophenyl)-1-phenylpyrazol-4-yl]acetyl chloride Chemical compound ClC(=O)CC1=CN(C=2C=CC=CC=2)N=C1C1=CC=C(Cl)C=C1 YSQLFGQECCZYNG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 229910014033 C-OH Inorganic materials 0.000 description 1
- 208000004434 Calcinosis Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229910014570 C—OH Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VIRXTVKQSONSCM-UHFFFAOYSA-N [2-[5-(4-chlorophenyl)-2-phenyl-1h-pyrazol-5-yl]-1-hydroxy-1-phosphonoethyl]phosphonic acid Chemical compound C1=CC(CC(O)(P(O)(O)=O)P(O)(O)=O)(C=2C=CC(Cl)=CC=2)NN1C1=CC=CC=C1 VIRXTVKQSONSCM-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000002449 bone cell Anatomy 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000003913 calcium metabolism Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 description 1
- IQRYPZXSRARLGV-UHFFFAOYSA-L disodium [1-[4-(4-chlorophenyl)-1-(4-fluorophenyl)pyrazol-3-yl]-2-hydroxy-2-phosphonatoethyl]phosphonic acid Chemical compound [Na+].[Na+].ClC1=CC=C(C=C1)C=1C(=NN(C=1)C1=CC=C(C=C1)F)C(C(P([O-])(=O)[O-])O)P(O)(=O)O IQRYPZXSRARLGV-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/65031—Five-membered rings having the nitrogen atoms in the positions 1 and 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
Description
Phosphonate, und diese enthaltendePhosphonates, and containing them
pharmazeutische Verbindungen Die Erfindung betrifft die in den Patentansprüchen gekennzeichneten Phosphonate und pharmazeutische Präparate, die diese Verbindungen enthalten.pharmaceutical compounds The invention relates to the phosphonates and pharmaceutical preparations characterized in the patent claims, which contain these compounds.
Die erfindungsgemäßen Verbindungen haben ebenso wie die Carbonsäuren der Formel III AR-CH,COOH (in dieser Formel wie auch in den nachfolgenden werden die Substituenten stets so definiert wie im Patentanspruch 1) - siehe Deutsche Offenlegungsschriften-26 05 243 und 26 33 992 - eine ausgeprägte antiinflammatorische und antiarthritische Wirksamkeit. Gegenüber diesen Substanzen zeichnen sie sich aber dadurch aus, daß sie unter anderem imstande sind, die Aufbau- und Abbau-Leistung der Knochenzellen (Osteoblasten/Osteoklasten) so zu beeinflussen, daß kurative Effekte bei Ratten mit induzierter Arthritis eindeutig nachweisbar sind.Like the carboxylic acids, the compounds according to the invention have of the formula III AR-CH, COOH (in this formula as well as in the following ones the substituents are always defined as in claim 1) - see German Offenlegungsschriften-26 05 243 and 26 33 992 - a pronounced anti-inflammatory and anti-arthritic Effectiveness. They are distinguished from these substances by the fact that They are able, among other things, to increase the structure and breakdown performance of the bone cells (Osteoblasts / osteoclasts) to influence so that curative effects in rats with induced arthritis are clearly detectable.
Mit dieser antiarthritischen Wirksamkeit der erfindungsgemäßen Verbindungen ist die Grundlage für eine Therapie der Rheumatoiden Arthritis, der Osteoarthritis, Spondylitis ankylosans und anderer verwandter Erkrankungen, besonders des Kollagens und des Skelettsystems (Osteoporose, Pagetskrankheit) geschaffen. Darüber hinaus können die Phosphonate als gute Komplexbildner für Calcium überall dort therapeutisch sinnvoll eingesetzt werden, wo ein gestörter Ca-Stoffwechsel als Ursache für eine Erkrankung erkannt wurde, z.B. bei cardiovaskulären Erkrankungen, ektopischen Calcifikationen etc..With this anti-arthritic effectiveness of the compounds according to the invention is the basis for a therapy for rheumatoid arthritis, osteoarthritis, Ankylosing spondylitis and other related diseases, especially collagen and the skeletal system (osteoporosis, Paget's disease). Furthermore The phosphonates can be used therapeutically everywhere as good complexing agents for calcium can be used sensibly where a disturbed Ca metabolism is the cause of a Disease was recognized, e.g. in cardiovascular diseases, ectopic calcifications Etc..
Die Verbindungen können in Form ihrer Ester, Halbester - vorzugsweise jedoch in Form der freien Phosphonsäuren bzw. deren physiologisch verträglichen Salzen mit Alkali-, Erdalkalihydroxiden oder verträglichen organischen Basen - angewendet werden. Als galenische Formulierungen sind Kapseln, Tabletten, Dragees, Suppositorien, aber auch Injektionslösungen und dermale Zubereitungen geeignet. Auch eine lokale Anwendung zur Behandlung dermaler oder systemischer Erkrankungen ist möglich.The compounds can be in the form of their esters, half esters - preferably however, in the form of the free phosphonic acids or their physiologically compatible ones Salts with alkali, alkaline earth hydroxides or compatible organic bases - applied will. Galenic formulations are capsules, tablets, coated tablets, suppositories, but also injection solutions and dermal preparations are suitable. Also a local one Use for the treatment of dermal or systemic diseases is possible.
Die Herstellung der Phosphonate erfolgt nach Methoden wie sie dem Fachmann wohlbekannt sind (Hcuben-Weyl, Methoden der organischen Chemie, Georg Thieme Verlag Stuttgart 4. Auflage, 1963 Band XII/1,453 ff) und welche in den nachfolgenden Schemata dargestellt sind.The production of the phosphonates takes place according to methods like them Those skilled in the art are well known (Hcuben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag Stuttgart 4th edition, 1963 Volume XII / 1.453 ff) and which in the following Schemas are shown.
Schema 1
Beispiel 1 16.5 g 4-(4-Chlorphenyl)-l-(4-fluorphenyl) -3-pyrazolessigsäure werden in 400 ml Diethylether auf - 150C gekühlt und portionsweise mit 14.6 g Phosphorpentachlorid versetzt.Example 1 16.5 g of 4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid are cooled to - 150 ° C. in 400 ml of diethyl ether and mixed in portions with 14.6 g of phosphorus pentachloride offset.
Man rührt die Mischung 2.5 Stunden lang bei -150C und weitere 2.5 Stunden bei OOC. Dann engt man die klare Lösung weitgehend im Vakuum ein, verrührt den öligen Rückstand mit Benzin (Siedebereich 40-600C) und erhält 16 g 4-(4-Chlorphenyl) l-(4-fluorphenyl)-3-pyrazolessigsäurechlorid vom Schmelzpunkt 93-950C.The mixture is stirred for 2.5 hours at -150 ° C. and for a further 2.5 hours Hours at OOC. The clear solution is then largely concentrated in vacuo and stirred the oily residue with gasoline (boiling range 40-600C) and receives 16 g of 4- (4-chlorophenyl) 1- (4-fluorophenyl) -3-pyrazole acetic acid chloride, melting point 93-950C.
Eine Lösung von 17.5 g 4-(4-Chlorphenyl)-l-(4-fluorphenyl) -3-pyrazolessigsäurechlorid in 100 ml Tetrahydrofuran wird auf 1ODC gekühlt und mit 9.8 ml Triethylphosphit versetzt. Man rührt noch 3 Stunden lang bei 10-150C, engt die Lösung im Vakuum ein und kristallisiert den öligen Rückstand aus Diisopropylether. Man erhält 18.8 g (83.47o) 2-[4-(4-Chlorphenyl)-l-(4-fluorphenyl)-3-pyrazolyl]-lhydroxy-ethen-phosphonsäure-diethylester vom Schmelzpunkt 96-980C.A solution of 17.5 g of 4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid chloride in 100 ml of tetrahydrofuran is cooled to 1ODC and with 9.8 ml of triethyl phosphite offset. The mixture is stirred for a further 3 hours at 10-150 ° C. and the solution is concentrated in vacuo and the oily residue crystallized from diisopropyl ether. 18.8 g are obtained (83.47o) 2- [4- (4-Chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] -l-hydroxy-ethene-phosphonic acid diethyl ester of melting point 96-980C.
Beispiel 2 Eine Mischung von 1.27 g 2-[4-(4-Chlorphenyl)-l-(4-fluorphenyl ) -3-pyrazolyl] 1-hydroxy-ethen-phosphonsäure-diethylester in 5 ml Tetrachlorkohlenstoff wird bei 0°C unter Stickstoff mit 1.3 g Jodtrimethylsilan versetzt und anschließend eine Stunde lang bei Raumtemperatur gerührt.Example 2 A mixture of 1.27 g of 2- [4- (4-chlorophenyl) -1- (4-fluorophenyl ) -3-pyrazolyl] 1-hydroxy-ethene-phosphonic acid diethyl ester in 5 ml of carbon tetrachloride 1.3 g of iodotrimethylsilane are added at 0 ° C. under nitrogen and then stirred for one hour at room temperature.
Man engt die Mischung im Vakuum ein, versetzt den Rückstand mit Wasser und Aceton, rührt noch 30 Minuten lang und kristallisiert das ausgefallene Produkt aus Ethanol um. Man erhält so 0.82 g (74,2 5) 2-[4-(4-Chlorphenyl) 1- (4-fluorphenyl) -3-pyrazolyl] -l-hydroxy-ethen-phosphonsäure vom Schmelzpunkt 238-240°C.The mixture is concentrated in vacuo, and water is added to the residue and acetone, stir for a further 30 minutes and the precipitated product crystallizes from ethanol. This gives 0.82 g (74.2 5) 2- [4- (4-chlorophenyl) 1- (4-fluorophenyl) -3-pyrazolyl] -l-hydroxy-ethene-phosphonic acid with a melting point of 238-240 ° C.
Beispiel 3 Eine Mischung von 24 g 4-(4-Chlorphenyl)-l-(4-fluorphenyl) -3-pyrazolessigsäure mit 4 ml Wasser und 180 ml Phosphortrichlorid wird 5 Stunden lang auf 1200C (Badtemperatur) erhitzt. Nach Abdestillieren des überschüssigen Phosphortrichlorids wird der Rückstand vorsichtig mit 400 ml Wasser versetzt und drei Stunden lang im Dampfbad erhitzt. Dann läßt man die Mischung erkalten, saugt das Kristallisat ab und trocknet es. Dann wird es mit erwärmten Toluol extrahiert und man gewinnt aus dem Toluolextrakt 7.5 g Ausgangsmaterial zurück. Der Rückstand wird aus Isopropylalkohol und dann aus Ethanol umkristallisiert. Man erhält 11,1 g (bei Berücksichtigung des zurückgewonnenen Ausgangsmaterials 57) 2-[4 -(4-Chlorphenyl)-l-(4-fluorphenyl)-3-pyrazolyl]-l-hydroxy-ethen-phosphonsäure vom Schmelzpunkt 238-2400C.Example 3 A mixture of 24 g of 4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid with 4 ml of water and 180 ml of phosphorus trichloride is 5 hours heated to 1200C (bath temperature) for a long time. After distilling off the excess phosphorus trichloride the residue is carefully mixed with 400 ml of water and immersed for three hours Steam bath heated. The mixture is then allowed to cool and the crystals are filtered off with suction and dry it. Then it is extracted with heated toluene and recovered the toluene extract back 7.5 g of starting material. The residue is made from isopropyl alcohol and then recrystallized from ethanol. 11.1 g are obtained (taking into account the Recovered Starting Material 57) 2- [4 - (4-Chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] -1-hydroxy-ethene-phosphonic acid of melting point 238-2400C.
Beispiel 4 Eine Mischung von 0.6 g Triethylphosphit und 0.2 g Triethylamin wird bei OOC mit 1.4 g 4-(4-Chlorphenyl)-l-(4-fluorphenyl)-3-pyrazolessigsäurechlorid - gelöst in 5 ml Dichlormethan - versetzt. Die Mischung wird eine Stunde bei OOC und eine weitere Stunde bei Raumtemperatur gerührt. Dann engt man im Vakuum ein und kristallisiert den Rückstand aus Diethylether und anschließend aus Ethanol.Example 4 A mixture of 0.6 g of triethyl phosphite and 0.2 g of triethylamine is at OOC with 1.4 g of 4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid chloride - dissolved in 5 ml dichloromethane - added. The mixture is at OOC for one hour and stirred for a further hour at room temperature. Then you concentrate in a vacuum and the residue crystallizes from diethyl ether and then from ethanol.
Man erhält so 1.02 g (66.8°6) 4-(4-Chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolessigsäure-(2-[4~(4-Chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolyl]-1-(diethoxyphosphonyl)-vinyl) ester vom Schmelzpunkt 173-1740C.This gives 1.02 g (66.8 ° 6) 4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazole-acetic acid- (2- [4 ~ (4-chlorophenyl) -1- (4-fluorophenyl) - 3-pyrazolyl] -1- (diethoxyphosphonyl) vinyl) esters of melting point 173-1740C.
Beispiel 5 Zu einer Mischung von 0.9 g 4-(4-Chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolessigsäure-{2-[4-(4-chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolyl]-1-(diethoxyphosphonyl)-vinylJester in 12 ml Tetrachlorkohlenstoff wird unter Stickstoff bei OOC 0.56 g Jodtrimethylsilan eingetropft. Man rührt eine Stunde lang bei Raumtemperatur und arbeitet das Reaktionsgemisch auf, wie im Beispiel 2 beschrieben, kristallisiert das Rohprodukt aus Isopropylalkohol um und erhält 0.61 g (71,8) 4-(4-Chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolessigsäure-{2-[4-(4-chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolyl]-l-phosphonyl-vinylester vom Schmelzpunkt 129-1310C.Example 5 To a mixture of 0.9 g of 4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazole-acetic acid- {2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3- pyrazolyl] -1- (diethoxyphosphonyl) vinyl jester 0.56 g of iodotrimethylsilane is added to 12 ml of carbon tetrachloride under nitrogen at OOC dripped in. The reaction mixture is stirred for one hour at room temperature on, as described in Example 2, the crude product crystallizes from isopropyl alcohol and receives 0.61 g of (71.8) 4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid- {2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) - 3-pyrazolyl] -l-phosphonyl vinyl ester of melting point 129-1310C.
Beispiel 6 Zu einer Lösung von 5.7 , 7 g Diethylphosphit und 4.-6 ml Diethylamin in 30 ml Tetrahydrofuran wird bei 0°C eine Lösung von 18 g 2-[4-(4-Chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolyl]-1-hydroxy-ethen-phosphonsäure-diethylester in 40 ml Tetrahydrofuran eingetropft, und die Mischung 5 Stunden lang bei 0-50C gerührt. Man engt das Gemisch im Vakuum ein, kristallisiert aus Diethylether und dann aus Tetrachlorkohlenstoff um und erhält 15.2 g (64,4°a) 2-[4-(4-Chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolyl]-1-hydroxyethan-1,1-bis(phosphonsäurediethylester) vom Schmelzpunkt 141-1420C.Example 6 To a solution of 5.7.7 g of diethyl phosphite and 4.-6 ml of diethylamine in 30 ml of tetrahydrofuran is a solution of 18 g of 2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] -1-hydroxy-ethene-phosphonic acid diethyl ester at 0 ° C. added dropwise in 40 ml of tetrahydrofuran, and the mixture for 5 hours at 0-50C touched. The mixture is concentrated in vacuo and crystallized from diethyl ether and then from carbon tetrachloride and receives 15.2 g (64.4 ° a) 2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] -1-hydroxyethane-1,1-bis (diethyl phosphonate ) of melting point 141-1420C.
Beispiel 7 11.8 g 2-[ 4-(4-Chlorphenyl)-l-(4-fluorphenyl)-3-pyrazolyl] l-hydroxyethan-l,l-bis(phosphonsäurediethylester) werden mit 5 Äquivalenten Jodtrimethylsilan umgesetzt und aufbereitet, wie in Beispiel 2 beschrieben. Das erhaltene Rohprodukt wird mit wässrigem Ethanol gewaschen, aus Ethanol umkristallisiert und man erhält 8.0 g (84°ó) 2-[4-(4-Chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolyl]-1-hydroxyethan-1,1-diphosphonsäure vom Schmelzpunkt 202-2040C.Example 7 11.8 g of 2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] L-hydroxyethane-l, l-bis (phosphonic acid diethyl ester) are treated with 5 equivalents of iodotrimethylsilane implemented and processed as described in Example 2. The crude product obtained is washed with aqueous ethanol, recrystallized from ethanol and obtained 8.0 g (84 ° ó) 2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] -1-hydroxyethane-1,1-diphosphonic acid of melting point 202-2040C.
Beispiel 8 0.59 g 2-[4-(4-Chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolyl]-l-hydroxyethan-l,l-bis(phosphonsäurediethylester) werden mit 4 ml 63 prozentiger Bromwasserstoffsäure versetzt und zwei Stunden lang auf 1000C erhitzt. Dann verdünnt man das Gemisch mit Wasser und läßt es erkalten. Das erhaltene Rohprodukt wird zerkleinert, aus Ethanol umkristallisiert und man erhält 0.37 g (77) 2-[4-(4-Chlorphenyl)-l-(4-fluorphenyl)-3-pyrazolyl]-1-hydroxyethan-1,1-diphosphonsäure vom Schmelzpunkt 201-2030C.Example 8 0.59 g of 2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] -l-hydroxyethane-1,1-bis (diethyl phosphonate) 4 ml of 63 percent hydrobromic acid are added and the mixture is carried out for two hours heated to 1000C. The mixture is then diluted with water and allowed to cool. The crude product obtained is crushed, recrystallized from ethanol and one obtained 0.37 g of (77) 2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] -1-hydroxyethane-1,1-diphosphonic acid of melting point 201-2030C.
Beispiel 9 Eine Lösung von 1.9 g 2-[4-(4-Chlorphenyl)-l-(4-fluor phenyl)-3-pyrazolyl]-1-hydroxyethan-1,1-diphosphonsäure in 5 ml Dimethylformamid wird mit einer Lösung von 0.8 g Natriumhydrogencarbonat in 10 ml Wasser versetzt und zwei Stunden lang bei Raumtemperatur gerührt. Man saugt das abgeschiedene Produkt ab, wäscht es mit wenig Wasser, trocknet es bei 110°C und erhält 1.6 g (76°ó) 2-[4-(4-Chlorphenyl) -l-(4-fluorphenyl)-3-pyrazolyl] lhydroxyethandiphosphonsäure-Dinatriumsalz vom Schmelzpunkt oberhalb 3000C.Example 9 A solution of 1.9 g of 2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] -1-hydroxyethane-1,1-diphosphonic acid in 5 ml of dimethylformamide is mixed with a solution of 0.8 g of sodium hydrogen carbonate added in 10 ml of water and stirred for two hours at room temperature. Man sucks the deposited product, washes it with a little water, dries it at 110 ° C and receives 1.6 g (76 ° ó) 2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] 1-hydroxyethanediphosphonic acid disodium salt from the melting point above 3000C.
Beispiel 10 Eine Lösung von 4,7 g 4-(4-Chlorphenyl)-l-(4-fluorphenyl)-3-pyrazolyl-acetonitril in 25 ml Dioxan wird mit einer Lösung von 12.8 g Phosphortribromid in 10 ml Dioxan und mit 4 g Phosphorigesäure versetzt und 30 Minuten lang bei Raumtemperatur und dann 10 Stunden lang bei 60 bis 700C (Badtemperatur) gerührt. Dann destilliert man das Dioxan im Vakuum ab, versetzt mit Wasser und rührt eine Stunde lang. Der ausgefallene Niederschlag wird mehrfach mit Ethylacetat-Methanol gewaschen, und dann aus Dioxan-Wasser umkristallisiert. Man erhält so 3.3 g (46so) 1-Amino-2-[4-(4-chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolyl] -ethan-l.l-diphosphonsäure vom Schmelzpunkt 251-2550C.Example 10 A solution of 4.7 g of 4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl-acetonitrile in 25 ml of dioxane is mixed with a solution of 12.8 g of phosphorus tribromide in 10 ml of dioxane and treated with 4 g of phosphorous acid and for 30 minutes at room temperature and then stirred for 10 hours at 60 to 700C (bath temperature). Then you distill the dioxane is removed in vacuo, water is added and the mixture is stirred for one hour. The unusual one The precipitate is washed several times with ethyl acetate-methanol, and then from dioxane-water recrystallized. 3.3 g of (46so) 1-amino-2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] are obtained in this way. -ethane-1.l-diphosphonic acid with a melting point of 251-2550C.
Beispiel 11 Eine Mischung von 3.02 g [4-(4-Chlorphenyl)-l-(4-fluorphenyl) -3-pyrazolyl] -methanol und 15 g Mangandioxyd (E.Example 11 A mixture of 3.02 g of [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] -methanol and 15 g manganese dioxide (E.
Merck AG Darmstadt, gefällt, aktiv) in 100 ml Chloroform wird drei Stunden lang bei Raumtemperatur gerührt. Dann filtriert man die Reaktionsmischung über Kieselgur, wäscht mit Chloroform nach, engt das Filtrat im Vakuum ein und kristallisiert den Rückstand aus Cyclohexan. Man erhält so 2.78 g (92,7) 4-(4-Chlorphenyl)-l-(4-fluorphenyl)-pyrazol-3-carbaldehyd vom Schmelzpunkt 146-1480C.Merck AG Darmstadt, like, active) in 100 ml of chloroform turns three Stirred for hours at room temperature. The reaction mixture is then filtered over kieselguhr, rewashed with chloroform, the filtrate concentrated in vacuo and crystallized the residue from cyclohexane. 2.78 g (92.7) 4- (4-chlorophenyl) -1- (4-fluorophenyl) pyrazole-3-carbaldehyde are obtained in this way of melting point 146-1480C.
Eine Lösung von- 4.93 g Titantetrachlorid in 6 ml Tetrachlorkohlenstoff wird bei OOC in 50 ml Tetrahydrofuran eingetropft. Dann fügt man noch 3.91 g 4-(4-Chlorphenyl)-1-(4-fluorphenyl)-pyrazol-3-carbaldehyd und anschließend 3.75 g 6.91 g Methan-bis(phosphonsäurediethylester) zu und tropft in die Mischung eine Lösung von 5.26 g N-Methylmorpholin in 9 ml Tetrahydrofuran. Man rührt die Reaktionsmischung eine Stunde lang bei 0°C und anschließend vier Stunden lang bei Raumtemperatur, versetzt sie mit Dichlormethan und hydrolysiert mit 1 N Salzsäure. Die organische Phase wird abgetrennt, mit Wasser gewaschen und im Vakuum eingeengt. Der Rückstand wird mehrfach mit heißem Diisopropylether extrahiert, zweimal aus Cyclohexan umkristallisiert und man erhält 5k7 g (76,7%) 2-[ 4-(4-Chlorphenyl)-l-(4-fluorphenyl)-3-pyrazolylJ-vinyliden-l,l-bis(phosphonsäure-diethylester) vom Schmelzpunkt 119-1210 C.A solution of 4.93 g of titanium tetrachloride in 6 ml of carbon tetrachloride is added dropwise to 50 ml of tetrahydrofuran at OOC. Then 3.91 g of 4- (4-chlorophenyl) -1- (4-fluorophenyl) pyrazole-3-carbaldehyde are added and then 3.75 g of 6.91 g of methane bis (diethyl phosphonate) and a solution of 5.26 g of N-methylmorpholine in 9 ml of tetrahydrofuran is added dropwise to the mixture. The reaction mixture is stirred for one hour at 0 ° C. and then for four hours long at room temperature, it is treated with dichloromethane and hydrolyzed with 1N Hydrochloric acid. The organic phase is separated off, washed with water and in vacuo constricted. The residue is extracted several times with hot diisopropyl ether, twice recrystallized from cyclohexane and one receives 5k7 g (76.7%) 2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolylJ-vinylidene-1,1-bis (phosphonic acid diethyl ester) from melting point 119-1210 C.
Beispiel 12 2-[4-(4-Chlorphenyl)-l-(4-fluorphenyl)-3-pyrazolyl]-vinyliden-l,l-bis(phosphonsäure-diethylester) wird analog Beispiel 7 beschrieben mit Jodtrimethylsilan umgesetzt, aufbereitet und man erhält in 95%iger Ausbeute die 2-E 4-(4-Chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolyl]-vinyliden-l.l-diphosphonsäure vom Schmelzpunkt 253-2550C (Ethylacetat).Example 12 2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] vinylidene-1,1-bis (diethyl phosphonate) is reacted with iodotrimethylsilane as described in Example 7, worked up and 2-E 4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] vinylidene-l-diphosphonic acid is obtained in 95% yield of melting point 253-2550C (ethyl acetate).
Beispiel 13 Eine Lösung von 1.42 g 2-[4-(4 -Chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolyl]-vinyliden-l.1-bis(phosphonsäurediethylester) in 100 ml Ethanol wird in Gegenwart von 200 mg Palladium-Kohle bei Raumtemperatur hydriert.Example 13 A solution of 1.42 g of 2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] vinylidene-1.1-bis (diethyl phosphonate) in 100 ml of ethanol in the presence of 200 mg of palladium-carbon at room temperature hydrogenated.
Nach Beendigung der Wasserstoffaufnahme wird der Katalysator abfiltriert, der Rückstand aus Tetrachlorkohlenstoff umkristallisiert und man erhält 1,2 g (85,5) 2-[4-(4-Chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolyl] -ethan-1.l-bis(phosponsäure-diethylester) vom Schmelzpunkt 128-1300C.After the uptake of hydrogen has ended, the catalyst is filtered off, the residue is recrystallized from carbon tetrachloride and 1.2 g (85.5) are obtained 2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] ethane-1.l-bis (diethyl phosphonate) of melting point 128-1300C.
Beispiel 14 Eine Lösung von 2.56 g 2-[4-(4-Chlorphenyl)-1-(4-fluorphenyl)-3-pyrazolyl] -vinyliden-l.l-bis(phosphonsäurediethylester) in 30 ml Ethanol wird mit 110 mg Natriumborhydrid versetzt und unter Eiskühlung zwei Stunden lang gerührt. Dann setzt man der Reaktionsmischung Natriumdihydrogenphosphat zu und extrahiert mit Dichlormethan. Man engt die organische Phase ein, kristallisiert aus Cyclohexan um und erhält 2.33 g (90,450) 2-[4-(4-Chlorphenyl )-l-(4-fluorphenyl ) -3-pyrazolyl] -ethanl.l-bis(phosphonsäure-diethylester) vom Schmelzpunkt 128-1310C.Example 14 A solution of 2.56 g of 2- [4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] Vinylidene-1.l-bis (phosphonic acid diethyl ester) in 30 ml of ethanol is mixed with 110 mg of sodium borohydride added and stirred with ice-cooling for two hours. Then one sets the reaction mixture Sodium dihydrogen phosphate and extracted with dichloromethane. One narrows the organic Phase one, recrystallizes from cyclohexane and receives 2.33 g (90.450) 2- [4- (4-chlorophenyl ) -l- (4-fluorophenyl) -3-pyrazolyl] -ethanl.l-bis (phosphonic acid diethyl ester) from Melting point 128-1310C.
Beispiel 15 2-[4-(4-Chlorphenyl)-l-(4-fluorphenyl)-3-pyrazolyl]-ethan-l.l-bis(phosphonsäure-diethylester wird wie in Beispiel 7 beschrieben umgesetzt, aufbereitet und man erhält in 9050iger Ausbeute die 2-[4-(4-Chlorphenyl) 1.1-(4-fluorphenyl)-3-pyrazolyl]-ethan-1.1-diphosphonsäure vom Zersetzungspunkt oberhalb 2500C (Acetonitril).Example 15 2- [4- (4-Chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl] -ethane-1.1-bis (diethyl phosphonate is implemented as described in Example 7, processed and obtained in 9050iger Yield the 2- [4- (4-chlorophenyl) 1.1- (4-fluorophenyl) -3-pyrazolyl] ethane-1.1-diphosphonic acid from the decomposition point above 2500C (acetonitrile).
Beispiel 16 [3-(4-Chlorphenyl)-l-phenyl-4-pyrazolyl]-acetylchlorid wird wie in Beispiel 1 beschrieben mit Trimethylphosphit umgesetzt, aufbereitet und man erhält in 8050iger Ausbeute den 2-[3-(4-Chlorphenyl)-1-phenyl-3-pyrazolyl] l-hydroxy-ethen-phosphonsäure-dimethylester vom Schmelzpunkt 1740C (Diethylether).Example 16 [3- (4-Chlorophenyl) -1-phenyl-4-pyrazolyl] acetyl chloride is reacted as described in Example 1 with trimethyl phosphite, worked up and the 2- [3- (4-chlorophenyl) -1-phenyl-3-pyrazolyl] is obtained in 8050 yield L-hydroxy-ethene-phosphonic acid dimethyl ester with a melting point of 1740C (diethyl ether).
Beispiel 17 2-[3-(4-Chlorphenyl)-1-phenyl-4-pyrazolyl]-1-hydroxyethen-phosphonsäure-dimethylester wird wie in Beispiel 6 beschrieben mit Dimethylphosphit umgesetzt, aufbereitet und man erhält in 69 °Óiger Ausbeute den 2-[3-(4-Chlorphenyl)-l-phenyl-3-pyrazolyl]-1-hydroxy-ethan-1.1-bis-(phosphonsäure-dimethylester) vom Schmelzpunkt 1300 c.Example 17 2- [3- (4-Chlorophenyl) -1-phenyl-4-pyrazolyl] -1-hydroxyethene-phosphonic acid, dimethyl ester is reacted as described in Example 6 with dimethyl phosphite, processed and the 2- [3- (4-chlorophenyl) -l-phenyl-3-pyrazolyl] -1-hydroxy-ethane-1.1-bis (phosphonic acid dimethyl ester) is obtained in a yield of 69 ° from melting point 1300 c.
Beispiel 18 2-[3-(4-Chlorphenyl)-l-phenyl-4-pyrazolyl]-1-hydroxyethan-l.l-bis(phosphonsäure-dimethylester) wird wie in Beispiel 7 beschrieben umgesetzt, aufbereitet und man erhält in 78 %iger Ausbeute die 2-[3-(4-Chlorphenyl)-1-phenyl-3-pyrazolyl]-1-hydroxy-ethan-1.1-diphosphonsäure vom Schmelzpunkt 199° C.Example 18 2- [3- (4-chlorophenyl) -l-phenyl-4-pyrazolyl] -1-hydroxyethane-1.l-bis (phosphonic acid dimethyl ester) is reacted and worked up as described in Example 7 and is obtained in 78% strength Yield the 2- [3- (4-chlorophenyl) -1-phenyl-3-pyrazolyl] -1-hydroxy-ethane-1,1-diphosphonic acid with a melting point of 199 ° C.
Claims (18)
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0258618A2 (en) * | 1986-08-01 | 1988-03-09 | Roche Diagnostics GmbH | Diphosphonic acid derivatives, process for their preparation and medicines containing those compounds |
| EP0275821A1 (en) * | 1986-11-21 | 1988-07-27 | Ciba-Geigy Ag | Substituted alkanediphosphonic acids |
| US5434288A (en) * | 1992-12-01 | 1995-07-18 | Monsanto Company | PLA2 inhibitors |
| US7199113B2 (en) | 1998-09-25 | 2007-04-03 | Jin-An Jiao | Pharmaceutically active compounds and methods of use thereof |
| US7230116B2 (en) | 2001-10-22 | 2007-06-12 | Bayer Cropscience, Ag | Pyrazolyl-substituted heterocycles and their use as phytosanitary products |
| WO2020019108A1 (en) | 2018-07-23 | 2020-01-30 | Guangzhou Othrotx Co., Ltd. | Bisphosphonate drug conjugates |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2605243A1 (en) * | 1975-02-14 | 1976-09-02 | Byk Gulden Lomberg Chem Fab | Antirheumatic compsn. contg. pyrazole acetic acids - and dextropropoxyphen or tilidine as synergist to provide powerful, rapid and sustained analgesia |
| DE2633992A1 (en) * | 1975-08-08 | 1978-02-09 | Schering Ag | Antiinflammatory (1,4)-diphenyl-(3)-alkyl-carboxy-pyrazole - prepd. by treating corresp. (3)-halide with a cyanide, and opt. hydrolysing or reducing |
-
1982
- 1982-01-27 DE DE19823203307 patent/DE3203307A1/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2605243A1 (en) * | 1975-02-14 | 1976-09-02 | Byk Gulden Lomberg Chem Fab | Antirheumatic compsn. contg. pyrazole acetic acids - and dextropropoxyphen or tilidine as synergist to provide powerful, rapid and sustained analgesia |
| DE2633992A1 (en) * | 1975-08-08 | 1978-02-09 | Schering Ag | Antiinflammatory (1,4)-diphenyl-(3)-alkyl-carboxy-pyrazole - prepd. by treating corresp. (3)-halide with a cyanide, and opt. hydrolysing or reducing |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0258618A2 (en) * | 1986-08-01 | 1988-03-09 | Roche Diagnostics GmbH | Diphosphonic acid derivatives, process for their preparation and medicines containing those compounds |
| EP0258618A3 (en) * | 1986-08-01 | 1988-06-15 | Boehringer Mannheim Gmbh | Diphosphonic acid derivatives, process for their preparation and medicines containing those compounds |
| EP0275821A1 (en) * | 1986-11-21 | 1988-07-27 | Ciba-Geigy Ag | Substituted alkanediphosphonic acids |
| US4939130A (en) * | 1986-11-21 | 1990-07-03 | Ciba-Geigy Corporation | Substituted alkanediphosphonic acids and pharmaceutical use |
| US5434288A (en) * | 1992-12-01 | 1995-07-18 | Monsanto Company | PLA2 inhibitors |
| US5504237A (en) * | 1992-12-01 | 1996-04-02 | Monsanto Company | PLA2 inhibitors |
| US7199113B2 (en) | 1998-09-25 | 2007-04-03 | Jin-An Jiao | Pharmaceutically active compounds and methods of use thereof |
| US7230116B2 (en) | 2001-10-22 | 2007-06-12 | Bayer Cropscience, Ag | Pyrazolyl-substituted heterocycles and their use as phytosanitary products |
| US7435829B2 (en) | 2001-10-22 | 2008-10-14 | Bayer Cropscience Ag | Pyrazolyl-substituted heterocycles and their use as phytosanitary products |
| US7642359B2 (en) | 2001-10-22 | 2010-01-05 | Bayer Cropscience Ag | Pyrazolyl-substituted heterocycles and their use as phytosanitary products |
| US8058452B2 (en) | 2001-10-22 | 2011-11-15 | Bayer Cropscience Ag | Pyrazolyl-substituted heterocycles and their use as phytosanitary products |
| WO2020019108A1 (en) | 2018-07-23 | 2020-01-30 | Guangzhou Othrotx Co., Ltd. | Bisphosphonate drug conjugates |
| EP3827010A4 (en) * | 2018-07-23 | 2022-03-16 | Brise Pharmaceuticals Co., Ltd. | Bisphosphonate drug conjugates |
| US12049475B2 (en) | 2018-07-23 | 2024-07-30 | Brise Pharmaceuticals Co., Ltd. | Bisphosphonate drug conjugates |
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